Metastasectomy following incomplete response to high-dose interleukin-2.

OBJECTIVE: To evaluate our experience with metastasectomy following partial response or stable disease after treatment with high-dose interleukin-2 (HD IL-2). METHODS: A total of 305 patients with metastatic renal cell carcinoma or melanoma treated with HD IL-2 over a 12-year period were reviewed. Age, objective response, and overall survival data were evaluated using standard RECIST criteria and Kaplan-Meier estimates. RESULTS: The average age was 55.3 years (range, 15-85) and 245 (80.3%) patients had melanoma and 60 (19.7%) had renal cell carcinoma. The objective response rate to IL-2 for all patients was 13.6% and median survival was 16.8 months. Complete follow-up data were available for 236 patients with 147 (62.3%) progressing after treatment and 8 (3.3%) with a complete response. Incomplete responses were seen in 81 (34.3%) patients, including 57 (24.2%) patients with stable disease and 24 (10.1%) with partial responses. Of these 81 incomplete responders, 15 (18.5%) underwent subsequent metastasectomy. Patients without surgery had overall survival of 38.2 months and median survival has not yet been reached in those who underwent metastasectomy (P = 0.026). CONCLUSION: The data support prospective evaluation of metastasectomy following incomplete therapeutic responses to immunotherapy and defines a new role for surgical resection following IL-2 and perhaps other immunotherapy regimens.

The prognostic significance of stable disease following high-dose interleukin-2 (IL-2) treatment in patients with metastatic melanoma and renal cell carcinoma.

High-dose interleukin-2 (HD IL-2) is an approved immunotherapy agent for metastatic melanoma and renal cell carcinoma resulting in objective responses in 15-20 % of patients. An additional subset of patients achieves stable disease, and the natural history of these patients has not been well documented. We hypothesized that stable disease following HD IL-2 is associated with a survival advantage. To explore this hypothesis, a retrospective chart review of 305 patients diagnosed with metastatic melanoma or renal cell carcinoma treated with HD IL-2 was conducted. Patient characteristics, response based on standard RECIST criteria and overall survival were analyzed using the Kaplan-Meier method and associations with clinical response were compared using a log-rank test. Two hundred and forty-five patients had melanoma and 60 had renal cell carcinoma. Of these, 217 had complete data available for analysis. Fifty-nine percentage had progressive disease (PD), 26 % had stable disease (SD) and 15 % had an objective complete (CR) or partial response (PR). Median overall survival was 16.8 months for all patients with available survival data; patients with PD had a median survival of 7.9 months compared to 38.2 months for stable disease, while the median has not been reached for those with objective responses. This retrospective data support an association between overall survival and stable disease, suggesting that clinical benefit may be underestimated for patients treated with HD IL-2. The data further support the use of disease control rate (CR + PR + SD) as a more meaningful endpoint for future clinical studies of tumor immunotherapy, including future studies of HD IL-2.

Alzheimer's disease CSF biomarkers correlate with early pathology and alterations in neuronal and glial gene expression.

INTRODUCTION: Normal pressure hydrocephalus (NPH) patients undergoing cortical shunting frequently show early AD pathology on cortical biopsy, which is predictive of progression to clinical AD. The objective of this study was to use samples from this cohort to identify CSF biomarkers for AD-related CNS pathophysiologic changes using tissue and fluids with early pathology, free of post-mortem artifact. METHODS: We analyzed Simoa, proteomic, and metabolomic CSF data from 81 patients with previously documented pathologic and transcriptomic changes. RESULTS: AD pathology on biopsy correlates with CSF ß-amyloid-40/42, neurofilament light chain (NfL), and phospho-tau-181(p-tau181)/ß-amyloid-42, while several gene expression modules correlate with NfL. Proteomic analysis highlights 7 core proteins that correlate with pathology and gene expression changes on biopsy, and metabolomic analysis of CSF identifies disease-relevant groups that correlate with biopsy data.. DISCUSSION: As additional biomarkers are added to AD diagnostic panels, our work provides insight into the CNS pathophysiology these markers are tracking.

Talimogene Laherparepvec: Moving From First-In-Class to Best-In-Class.

Talimogene laherparepvec (T-VEC) is a modified oncolytic herpes Simplex virus, type 1 (HSV-1) encoding granulocyte-macrophage colony stimulating factor (GM-CSF). T-VEC is adapted for selective replication in melanoma cells and GM-CSF was expressed to augment host anti-tumor immunity. T-VEC is indicated for the local treatment of melanoma recurrent after primary surgery and is the first-in-class oncolytic virus to achieve approval by the FDA in 2015. This review will describe the progress made in advancing T-VEC to the most appropriate melanoma patients, expansion to patients with non-melanoma cancers and clinical trial results of T-VEC combination studies. Further, strategies to identify predictive biomarkers of therapeutic response to T-VEC will be discussed. Finally, a brief outline of high-priority future directions for investigation of T-VEC and other promising oncolytic viruses will set the stage for a best-in-class oncolytic virus to bring the maximum benefit of this emerging class of anti-cancer agents to patients with cancer.

An immune response characterizes early Alzheimer's disease pathology and subjective cognitive impairment in hydrocephalus biopsies.

Early Alzheimer's disease (AD) pathology can be found in cortical biopsies taken during shunt placement for Normal Pressure Hydrocephalus. This represents an opportunity to study early AD pathology in living patients. Here we report RNA-seq data on 106 cortical biopsies from this patient population. A restricted set of genes correlate with AD pathology in these biopsies, and co-expression network analysis demonstrates an evolution from microglial homeostasis to a disease-associated microglial phenotype in conjunction with increasing AD pathologic burden, along with a subset of additional astrocytic and neuronal genes that accompany these changes. Further analysis demonstrates that these correlations are driven by patients that report mild cognitive symptoms, despite similar levels of biopsy ß-amyloid and tau pathology in comparison to patients who report no cognitive symptoms. Taken together, these findings highlight a restricted set of microglial and non-microglial genes that correlate with early AD pathology in the setting of subjective cognitive decline.

Administration and Handling of Talimogene Laherparepvec: An Intralesional Oncolytic Immunotherapy for Melanoma.

PURPOSE/OBJECTIVES: To describe the administration and handling requirements of oncolytic viruses in the context of talimogene laherparepvec (Imlygic™), a first-in-class oncolytic immunotherapy.
. DATA SOURCES: Study procedures employed in clinical trials, in particular the OPTiM study.
. DATA SYNTHESIS: Evaluation of nursing considerations for administration of talimogene laherparepvec.
. CONCLUSIONS: Talimogene laherparepvec is administered through a series of intralesional injections into cutaneous, subcutaneous, or nodal tumors (with ultrasound guidance as needed) during an outpatient clinic visit. A single insertion point is recommended; however, multiple insertion points are acceptable if the tumor radius exceeds the needle's radial reach. Talimogene laherparepvec must be evenly distributed throughout the tumor through each insertion site. Talimogene laherparepvec requires storage at -90°C to -70°C and, once thawed, should be administered immediately or stored in its original vial and carton and protected from light in a refrigerator (2°C to 8°C). 
. IMPLICATIONS FOR NURSING: Because talimogene laherparepvec can be administered in the outpatient setting, nurses will be pivotal for appropriate integration and administration of this unique and effective therapy.